It is now well established that the mature brain is capable of mounting a reparative response as neural stem cells (NSCs) within the neurogenic regions of the brain, the subventricular zone and the hippocampus, proliferate and generate functional neurons under homeostatic condition and following brain insults. However, the regenerative potential of NSCs is diminished with aging. Thus far, the regulatory mechanisms which drive activation of regenerative NSCs during neuropathological conditions particularly following TBI is largely unknown. Furthermore, it is also unclear whether there is an age-related difference in regulating regenerative NSC response following brain injury. Developmental studies have established that Notch signaling pathway is essential for NSC maintenance, proliferation and survival during CNS development. Recent studies have also shown that Notch signaling is a key player for NSCs in the adult brain under homeostatic condition. As the injured brain recapitulates many aspects as the developing brain, we speculate that Notch signaling is likely the key regulator responsible for the activation and function of regenerative NSCs following brain injury and aging. In our preliminary studies, we have found that following brain injury, the expression level of Notch pathway proteins is elevated in the neurogenic regions in young adult brain which is correlated to the increased NSC proliferation and neurogenesis. In contrast, in the aged brain, the neurogenic regions display diminished expression of Notch pathway in normal condition and following TBI which parallels to the decreased NSC response in the aging brain. From these observations, we hypothesize that Notch signaling is necessary for activation of regenerative NSCs in the injured brain and reduced Notch signaling during aging contributes to the decreased regenerative response of NSCs in the aged brain following injury. To test this hypothesis, in Aim 1 of this proposal, we will determine the importance of Notch signaling in regenerative NSC response and functional recovery after TBI. In Aim 2, we will assess the significance of Notch signaling on regenerative NSCs on cellular learning, memory and plasticity in the hippocampus and olfactory bulb following TBI. In Aim 3, we will examine how Notch pathway activation in neurogenic niches affects the function of regenerative NSCs in the injured aged brain. As the significance of endogenous repair mechanism through NSCs in the adult brain is increasingly recognized and has attracted increasing interests for development of NSC-based therapies, it is necessary to understand the fundamental principles governing NSC activation under regenerative conditions. The goal of this proposal is to examine the regulatory signaling pathway responsible for regenerative NSC activation and functioning following TBI and aging with the focus on the role of Notch. .